Classification rationale

PVS1PM2 Likely Pathogenic

TET2 c.4164_4167del

The TET2 c.4164_4167del (p.Met1388IlefsTer59; p.M1388Ifs*59) variant has not been reported in ClinVar.¹ This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the 0.1% rarity threshold used for PM2 in non-VCEP review.² Published TET2 studies identified through curated review show that leukemia-associated TET2 alterations impair 5-hydroxymethylcytosine generation, and structural work supports the functional importance of the C-terminal catalytic region, which is consistent with loss of function as a disease-relevant mechanism for truncating variants.³ SpliceAI predicts no significant additional splice effect for this deletion, with a maximum delta score of 0.00; REVEL and BayesDel are not available for this variant type.⁴

PVS1 + PM2 → Likely Pathogenic

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 oncokb ↗PMID:21057493 ↗PMID:24315485 ↗pvs1_gene_context

4 spliceai ↗

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_001127208.2 · variants mapped to exon structure

TET2 NM_001127208.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong review Pathogenic

This variant is a frameshift deletion predicted to cause p.(Met1388IlefsTer59) and truncate the protein well before the normal C-terminus. Germline loss of function is supported as a disease-relevant mechanism for TET2, and the generic ClinGen SVI PVS1 framework supports applying PVS1 for this type of truncating variant.

Frameshift consequence p.(Met1388IlefsTer59)Generic PVS1 scaffold recommends default PVS1 for frameshift variants once LoF mechanism is establishedTET2 germline loss-of-function mechanism supported in gene context review

pvs1_generic_framework ↗

PM2 moderate review Pathogenic

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the non-VCEP PM2 threshold of 0.1% population frequency and supports rarity in reference populations.

Absent from gnomAD v2.1Absent from gnomAD v4.1

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 2 not met · 15 not assessed

Pathogenic

PS2 No confirmed de novo data were identified for this variant, so PS2 cannot be assessed.

PS3 Published TET2 functional studies were identified, but the retrieved evidence does not show a direct functional assay of this exact deletion.

PS4 No exact-variant case enrichment or case-control data were identified for this variant, so PS4 cannot be applied.

PM1 Available evidence does not establish that this variant lies in a confirmed mutational hotspot or a sufficiently defined critical region without benign variation, so PM1 is not assessed.

PM3 No data were identified showing this variant in trans with another pathogenic variant, so PM3 cannot be assessed.

PM6 No assumed de novo report was identified for this variant, so PM6 cannot be assessed.

PP1 No segregation data were identified for this variant, so PP1 cannot be assessed.

PP4 No phenotype information specific enough for PP4 was identified, so this criterion cannot be assessed.

PP5 No qualifying reputable-source pathogenic classification was identified for this exact variant, so PP5 is not assessed.

Benign

BA1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the 1% BA1 threshold and BA1 is not met.

BS1 This variant is absent from gnomAD v2.1 and gnomAD v4.1, so its population frequency is below the 0.3% BS1 threshold and BS1 is not met.

BS2 No evidence was identified showing this variant in healthy adult individuals in a manner suitable for BS2, so the criterion is not assessed.

BS3 Available evidence does not show well-established functional studies demonstrating a normal effect for this exact deletion, so BS3 cannot be applied.

BS4 No non-segregation data were identified for this variant, so BS4 cannot be assessed.

BP2 No data were identified showing this variant in cis with a pathogenic variant or in trans in a manner supporting BP2, so the criterion is not assessed.

BP5 No alternate molecular explanation for a specific phenotype was identified, so BP5 cannot be assessed.

BP6 No qualifying reputable-source benign classification was identified for this exact variant, so BP6 is not assessed.

N/A · 9 PS1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

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